Manufacture of esters of the hydrocinchona alkaloids.



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res dent of I,iErarikfort-on-thedflaih, Ger- 5 1 111; 'fiYfijiiYglitedcertain new anduseare]; Improvements, in the Manufacture of Esters ofthe Hydrocinchona Alkaloids, of which the following-is a specification.-

the esters. t the hydro-cinchona-alka- 1 loidsle, only,the;neetyl-hydroquinin: and a the acetyhhydroqinchonidin,are. known inthe i T amorphous state. -1 have now succeeded in produci giesters'of-hydro cinchonwalkalolds such as hydro-qu nin, hydrocmchonm,

15 h \"d1;.ocinchoni din,;-hydrocuprein-on hydroanequinl m sths'li y msioiomp acids, wh ch; 'est ers are easily drystalllzmg llli bl e edieamns c Ap srdmg .mqthlsnnvention I cause, for

a-lI St;EI,l Qe tilmghlfltids, or the anhydrids,-orthe pliegiol'esteiia- ;of; the organic acids, of.

.wlrieh-jt is desired toobtain the corresponding h diqcincliona-alkaloid esters, to react on t the; {correspondinghydrocinchona-alkagloidmgtheinsalts. or :their' oxy-magnesiumhaloid-eompoundsa or I. maystart from the.ein'cl1ona alkaloid esters andtreat these withthyrlrogen' in the. presence of metals ofthe-,mla-tihum;group, or (if colloidalzsolu- .gtions of these metals. i

- Tlae-flrydroci-nchona-alkaloid esters prethey have no bitter taste.

- The-.- "zfol lox\*-ingexamples illustrate the manner-infwlnch-thlsinventlon can be perzzfiormed.-butitrisif'not'limited to theseexamples-.1 The :pa-r-ts-are by weight.

lzh amyzle l iiHydroywi'n methyl-carbon- '-afc.-.32(3 rparts o'f'hydroquinin (one molecularzwi'ojiortiony are'dissoliied in 1600 partsANu -EAcTuRE or nsrnns OF T E mizocmcnolu A ne s Specification of,Letters Patent; Application 'filed l December 23, 1911. Serial No.667,447.-

iii-as of benzene, mixed with 108.5 .part's ofethyl ester ofchloroformic acid -(one m olecn lai'-'f proportion), and boiled for teriminutesf The resulting ester is thenestractdjwitlt dilute hydrochloricacid,-separated tfon'fthd 5%"- solution by means of ammonia andextracted with ether and then the greater-pawof-the ether. is distilledoil and the residueis mixed with petroleum-benzinr Onficoolingflhe 113 qdroquinin ethyl-carbonate separates in fine" 6t) colorless needles whichmelt atl-fi in 75 to"78. centi rade and are almost tasteless2' 'f-' Theydissolve readily in aleohol br ch'loro-I form, but aredifiicult-ly-soluble -in' -pet ro leum-benzin and wat'er.

Example ill:- Beizz-oyl-hydroqiaim'ni To \t-he Grignard' reactionproduct, obtained i'nfi the usual manner from 24.3 parts of mag nesium1000 parts of anhydrous ether-and 64.5 parts of-ethyl-chlorid 326 partseas droquinin are added and themixtur'e isflqee" aside and frequentlyshaken until the evo'l'ution of ethane has ceased. Then l40.'5-p'ar ts-=of benzoyl-chl0rid are added slowl and after the mixture has beenallowed to stand-* for several hours,'dilute 'hydrochlorie'aciW-f isadded, until all has dissolved-The aque: ous solution is then separatedfrom theethei"" and the base is separated by means ofa m monia andabsorbed in etl 'er.* On"being-80"*' allowed to stand theresulting-benzoyhhv f droquinin y allizes in large colorless iuidtasteless crystals which melt-- at. from 102 to 107-cent-igrade. Theyreadily diss'olve in alcohol and chloroform,but-'a-rQd-iliiultljfis*soluble in. pet-roleu-m-benzinand ivatrl "f The salicylate ofbenZOyLhydro'quinin precipitated inthe form of white needlgsf when theetherealv solution offthebasefiis'fl' mixed with salicylic acidandtliepreeipi-190 tate isp'urified by recrystalliz'i'ngfout'bfiialcohol, It melts at-froin 1-90 tof;193l5 cent-igra-de and is perfectlytasteless v Example [I]: SaZiayZ-hjylrdgiizne +326 M parts ofhydroqu'inin -(oncf molecularipro ffl s portion) are heatedwith2'14pfaits"o fsalol (one molecular proportion) oi-"prefers; with asmall excess thereof, fon aboiiitj .j hours to from to centigrade." Themeltis dissolved in 2000'partsofhot behgt'lroo" zene,.the resultingphenol is removed by shaking several times with dilute ammonia,

' i the base isextracted with dilute hydrochloric acid from the benzenesolution and the acid solution iswashed .with ether. By adding ammonia,the base is then separated from the 'acid liquor and is then absorbed inether.

On the ethereal solution being'allowed to stand the salicyl hydroquin inseparates outwater.

Example I V: Hydroguim'n -carb0nate..

To a-solution of 326 parts of hydroquinin *(one molecular proportion) in-3000 parts of chloroform, 100 parts of pyridin are added,- then, whilewellcooling, a solutiomof 495 parts of phosgene (half a molecularproportion) in'500 parts of chloroform is intro duced drop by drop. Thereaction product is shaken with 3000.parts 0f ice and an ex g bonate.1 0parts of quinin-ethyl-carbonate cess'of sulfuric .acid and after thechloroform having been separatedthe acid solution is precipitated bymeans of ammonia. The ammoniacal liquor-in whichthe pyridin is present,is drawn oil by suction andthe residue is dissolved in ether.The-ethereal solution is, afterdryingwith calcium chlorid, freed fromtheether by distillation, the residue dissolved in 3000 parts of absolutealcohol and mixed with 50 per cent. sulfuric 'acid, until acid sulfateof hydroquinin. carbonate no.longer separates out. This salt consists.of needle-shaped crystals which are readily soluble in waterbut-scarcely soluble in alcohol. After drawing off by suction andwashingfout the salt with alcohol, the

bisulfate is dissolved in ice water and shaken with ether and an excessof ammonia. By

evaporating the dried ether-"solution and triturating the residue, thehydroquinin carbonate is' obtained 'as a colorless and quite tastelesspowder. This powder readily dissolves in alcohol and-chloroform, but isdithcultly soluble in petroleum-benzin and water. Itforms a yellowheraathiteand is stable against permanganate in acid solution.

Example V Parami'rio-benzoyZ-hydroguim'n.-326 parts ofhydroquinin (onemolec- -ular proportion) are dissolved in-.3 kilo grams ofbenzene,'mixed with 185.5 parts'of para nitrobenzoyl'chlorid (onemolecular proportion) and'heated for a short time at boiling point.jWhemthe mass-has cooled, it is "extracted .by means of dilutehydrochloric acid and theacid solution is shaken with kilograms of etherand ammonia in excess. Para nitro-benzoyl-hydroquinin at once separatesout from the .etherin fine needles which are drawn off by suctionandExample V. M 1 4 'Ewample VIII: Hydro cinclwm'oi -et7zyZ- farerecrystallized out ofbe'nzene; forms light yellow colored-tastelessneedles' which are almost insolubleinether. and petroleumbenzin, verydiificultly soluble in cold ben zene and alcohol, more readily in hotalcohol and melt at from 163 to,164 Centigrade.-

In order to produce the ara-amino-benzoylsuction and recrystallized outof a mitlture of equal parts of benzene .and petrfl'iti'im benzin. Thepara-aminoebenzoyl-hy iifoquimin is thus obtained in colorless andtil'stel'ess needles which-melt at from '155 to 157.5

hydroquinin, 1 part- 0 para-nitro-benzoyl' centigrade and are readilysoluble in alcoholor chloroform butdifiicultly soluble in petr'-leum-benzin and water.

' Example VI H ydroquinin ethylm.

are dissolved in-14 parts of twenty percent.

sulfuricacid and. eighty parts of water-and mixed with a solution of 0.1part of colloidal palladium 'in 10parts of water, Then'the .mixture isshaken with hydrogen at apres sure of 3 meters of water, untilnomore'hydrog'en is absorbed. The liquor is then mixed with ammonia in.excess and the base is extracted with ether. The residue remaining ondistilling oil the ether is dissolved in one hundred parts of hotpetroleum-benzin. On cooling the solution the hydroquininethyl-carbonatecrystallizes in Lfine needles which possess the properties describedunder the foregoing Example I.

' Example 'Vll Para amino benzo'yl hydro uiaia. partsofpa-ra-amino-benzoy -qu 1n1n are dissolved in 400" parts of water and 30parts of Sulfuric acid, 1 part l of palladium black is added and themixture isshaken with hyrogen until the gas ceases to beabsorbed.Thenthe palladium. I

is separated by filtration, the base preci i-- tated with ammonia andrecrystallization, effected in benzene-benzin. The body thus obtainedhas the properties described in carbonat.-'30 parts ofcinchonin-ethylscar bonate are dissolved in 160 parts -of alcohol;

the mixture is mixed with a solution of 0.1

water and shaken with hydrogen at a presvolume "of the hydrogen nolonger 'decreases.

part of colloidal palladium 'in 60"parts. 0i

The greater part of the alcohol is then dis- 7.

tilled oil, and the residue is dissolved in dilute sulfuric acidso thatthe palladium is recipitated. The mass is filtered and the ltr'atemixedwith ammonia in excess and the base is absorbed in ether. Afterdistilling oil the ,ether the mass is dissolved in dilute alcohol out ofwhich the hydrocinchonin-ethyl-carbonate crystallizes in fine,

. colorless and tasteless needleswhich melt at 134i centigrade. It isreadily soluble in alcohol or chloroform, but is diiiicultly soluble inpetroleum-benzin and water. In sul-' chlorid are successively added andthe mass is heated for a short time at the boiling point. After coolingthe chloroform solution is extracted with very dilute sulfuric acid andthe acid solution is precipitated with soda lye and subjected tosuction,

washed with water and the residue is absorbed in ether. After drying theethereal solution with calcium chlorid, the benzoylhydrocupreinseparates out in colorless crystals which are purified byrecrystallization from benzene. The melting point is 172 centigrade.This product is readily soluble in alcohol or chloroform, but isdiiiicultly soluble, in petroleum benzin and water.

Example X: De'benzoylhydrocupreim- To a solution of 416 parts ofbenzoyl-hydrocuprein in about 2-100 parts of henzone are added 140.5parts of benzoyl-chlorid and the mixture is heated for a short time atboiling point. After cooling, the new base is extracted by means ofhydrochloric acid, and the acid solution precipitated-with ammonia. Theprecipitate is drawn off by suction and dissolred in 2000 After thesolution has cooled, the dibenzoyl-hydrocuprein crystallizes out in finecolorless needles which melt at 1%? centigrade and are readily solublein alcohol and chloroform, but ditficultly soluble in petroleum-benzina'ndwater.

Ea'ample XI Ethyl-hydroGawain-ethylcarb0nate.3 i0 parts ofethyl-hydrocuprein are dissoli'ed in 3 1-00 parts of benzene,mixed with108.5 parts of ethyl ester of chloroformic acid and heated for a shorttime at boiling point. mixture is extracted with dilute hydrochloricacid, and the base dissolved in the acid is precipitated by means ofammonia and absorbed with ether. The base is preferably, converted intoits readily crystallizable salicylate by adding salicylic acid to theetheral solution of the base dried with calcium chlorid until thereaction becomes acid. On being left to stand (after preliminaryconcentration if required) the sali- After cooling, the reaction acylate er ethyl-hydrocuprein-ethyl-carbonate crystallizes in colorlesscrystals, which melt .at from l3c to M2 Centigrade and are readilysoluble in alcohol and benzene but are more dithcultly soluble in etherand very dilhcult-ly soluble in petroleum-benzin. The

free base forms a colorless powder which is readily soluble in alcoholand chloroform,

but ditiicultly soluble in petroleum-benzin and water.

Having thus described the invention, whatis claimed and desired to besecured by Lettors-Patent is 1. The process of producing esters ofhydrocinchona alkaloids which comprises acidulating the correspondinghydrocinchona alkaloids with acid chlorids.

2, The process of producing esters of by droquinin which comprisesacidulating hydroquinin with acid chlorids.

3. The process of producing aromatic esters of hydrocinchona alkaloidswhich comprises acidulating with aromatic acidulating agents thecorresponding hydrocinchona alkaloids.

4. The process of producing aromatic esters of hydroquinin whichcomprises acidulating hydroquinin with aromatic acidulating agents.

5. The process of producing benzoyl esters of hydrocinchona alkaloidswhich comprises benzoylating the corresponding hydrocinchona alkaloids.

6. The process of producing benzoyl esters of hydroquinin whichcomprises benzoylating hydroquinin.

7. As new products the herein described aromatic esters of thehydrocinchona alkaloids, being colorless and tasteless bodies, which ingeneral are more stable toward po; tassium permanganate than thecorresponding cinchona alkaloid esters, and which are readily soluble inalcohol and chloroform but diflicultly soluble in petroleum benzin andwater.

8. As new products the herein described aromatic esters of hydroquinin,being colorless and tasteless bodies, which are in general more stabletoward potassium perman ganate than the corresponding quinin esters, andwhich are readily soluble in alcohol and chloroform but diflicultlysoluble in petroleum benzin and water.

9. As new products the bcnzoic acid esters of the hydrocinchonaalkaloids, being col0r less and tasteless bodies, which are in generalmore stable toward potassium permanganate than the correspondingcinchona almore stable toward. potassium permanganate "but clifficultlysoluble inpe'troleum benzin 10 than the corresponding oinchona alkaloidesters, and which are readily soluble in alcohol and chloroformbutdifficultly soluble in petroleum benzin and water.

11. As a new product the benzoyl ester of hydroquinin, -being acolorless and tasteless body, forming crystals melting at 102-167" (1,readily soluble in alcohol and chloroform and Water.

In testimony whereof I have signed my name to this specification in thepresence of two subscribing witnesses.

HEINRICH THRON. Witnesses:

JEAN GRUND, CARL GRUND.

